WO2016010093A1 - Method for producing composite containing amorphous curcumin and/or analogue thereof - Google Patents
Method for producing composite containing amorphous curcumin and/or analogue thereof Download PDFInfo
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- WO2016010093A1 WO2016010093A1 PCT/JP2015/070318 JP2015070318W WO2016010093A1 WO 2016010093 A1 WO2016010093 A1 WO 2016010093A1 JP 2015070318 W JP2015070318 W JP 2015070318W WO 2016010093 A1 WO2016010093 A1 WO 2016010093A1
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- curcumin
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- hydroxypropylcellulose
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- BMXLYPNZUXYSER-YRLHZMKXSA-N COc(cc(/C=C/C(/C=C(/C=C/c(cc1OC)ccc1O)\O)O)cc1)c1O Chemical compound COc(cc(/C=C/C(/C=C(/C=C/c(cc1OC)ccc1O)\O)O)cc1)c1O BMXLYPNZUXYSER-YRLHZMKXSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Definitions
- the present invention relates to a method for producing a complex containing amorphous curcumin and / or an analog thereof.
- curcumin and its analogs have physiological activities such as tumor formation inhibitory action, antioxidant action, anti-inflammatory action, cholesterol lowering action, antiallergic action, brain disease prevention action, and heart disease prevention and treatment action.
- Application to foods for example, functional foods
- pharmaceuticals, cosmetics, and the like has been studied.
- curcumin and its analogs have a problem that the physiological activity of curcumin and its analogs cannot be sufficiently obtained by oral ingestion because their absorption into the body is extremely low.
- Patent Document 1 discloses that curcuminoids are made amorphous by melt-processing curcuminoids, thermoplastic polymers, and phosphatides, and the curcuminoids are made amorphous. A method for improving the absorption of curcuminoids into the body by ingesting the preparation is disclosed.
- Patent Document 2 discloses a water-soluble, branched or cyclic polysaccharide (modified edible starch, pectin, plant).
- a method for producing a curcumin complex in which rubber, propylene glycol alginate, cyclodextrin, maltodextrin derived from amylopectin and carboxymethylcellulose) are contacted in an aqueous solution having a pH of about 9 or more and acidified to have a pH of about 8 or less. Has been.
- the melt processing described in Patent Document 1 has a problem in that it is necessary to obtain a solid dispersion through a nozzle after heating and a special technique and apparatus are required and the manufacturing cost is high.
- the curcumin complex obtained in Patent Document 2 is used as a colorant for foods, and is used for the purpose of improving the absorption of curcumin and / or its analogs by ingestion into the body. It is not a thing. Further, it is not shown that the complex is amorphous.
- an object of the present invention is to provide an amorphous curcumin having a high content of curcumin and / or an analog thereof, and improving the absorption of curcumin and / or an analog thereof into the body by oral ingestion at low cost. And / or providing a method for producing a complex containing the analog at a high concentration.
- curcumin and / or its analogs that improve absorption into the body by oral ingestion.
- curcumin and / or its analogs and hydroxypropylmethylcellulose and / or hydroxypropylcellulose After dissolving both of these in an aqueous solution having a pH of 12 or more, the pH of the solution is adjusted to 7 or less.
- Amorphous curcumin and / or its analogs and hydroxy having significantly improved absorption in the body by oral ingestion. It discovered that the composite_body
- the present invention provides the following [1] to [5].
- [1] It comprises a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more, and a step of adjusting the pH of the solution to 7 or less.
- the amorphous curcumin according to [1] or [2] and / or the analog curcumin is at least one selected from the group consisting of bisdemethoxycurcumin, demethoxycurcumin and tetrahydrocurcumin A method for producing a complex of curcumin containing an analog and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
- the content ratio (A / B) of the curcumin and / or its analog (A) to the hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0.1 to 10.
- the content of curcumin and / or its analog is high, and curcumin and / or its analog and hydroxypropylmethylcellulose containing amorphous curcumin and / or its analog and / or A complex with hydroxypropylcellulose can be produced at a high concentration in a simple and inexpensive manner without the need for special techniques or equipment.
- a complex of curcumin and / or an analog thereof containing amorphous curcumin and / or an analog thereof prepared by the production method of the present invention is hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
- complex of curcumin and hydroxypropyl methylcellulose is shown.
- complex of curcumin and hydroxypropyl cellulose is shown.
- complex of curcumin and methylcellulose is shown.
- a method for producing a complex of curcumin and / or its analog containing hydroxycurcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose containing the amorphous curcumin of the present invention and / or its analog (1) a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more; (2) The step of adjusting the pH of the solution to 7 or less.
- Curcumin is a main component of curcuminoid contained in the turmeric pigment, and is a compound represented by the following structural formula (1).
- Curcumin used in the present invention may be chemically synthesized curcumin, or may be one that is distributed as a turmeric pigment.
- a turmeric pigment obtained by powdering dried rhizomes of ginger family turmeric (for example, Curcuma longa LINNE), the turmeric powder with an appropriate solvent (for example, ethanol, fat, propylene glycol, hexane, acetone, etc.) ), And crude curcumin or oleoresin (turmeric oleoresin) obtained by extraction with the use of) and purified curcumin.
- Curcumin includes both tautomeric keto type and enol type.
- curcumin analogs include demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin, dihydroxytetrahydrocurcumin and the like.
- the turmeric pigments include curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin.
- Hydroxypropyl methylcellulose is a water-soluble cellulose derivative in which part of the hydroxy group of cellulose is substituted with a methoxy group and a hydroxypropyloxy group.
- Various substitution degrees of the methoxy group and the hydroxypropyloxy group are known, and any of those usable as food can be used.
- Hydroxypropyl cellulose is a water-soluble cellulose derivative in which part of the hydroxy group of cellulose is substituted with a hydroxypropyloxy group.
- Various substitution degrees of hydroxypropyloxy groups are known, and any of those usable as food can be used.
- the mass ratio (A / B) of curcumin and / or its analog (A) and hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0 from the point of obtaining a complex having excellent oral absorbability. 0.02 to 10, preferably 0.03 to 10, more preferably 0.05 to 10, and still more preferably 0.1 to 10. Moreover, the containing mass ratio (A / B) in the obtained composite_body
- aqueous solutions having a pH of 12 or higher include alkaline aqueous solutions such as sodium hydroxide and potassium hydroxide. Of these, an aqueous sodium hydroxide solution is particularly preferred.
- the pH may be 12 or more, but is preferably pH 12 to 15, more preferably pH 12 to 14.
- the amount of curcumin and / or its analog added to an aqueous solution having a pH of 12 or higher is preferably such that it reaches a saturated concentration, preferably 0.1 g / 100 mL or more, and more preferably 0.1 to 10 g / 100 mL.
- curcumin and / or its analog (A) and (B) hydroxypropylmethylcellulose and / or hydroxypropylcellulose may be dissolved in an aqueous solution having a pH of 12 or more.
- the pH may be adjusted to 12 or more, and (A) and (B) may be added and dissolved in an aqueous solution having a pH of 12 or more.
- (A) may be added after adjusting the pH to 12 or higher, and (B) may be added after adjusting the aqueous dispersion of (A) to pH 12 or higher.
- the pH of the solution is adjusted to 7 or less.
- acids such as hydrochloric acid, a sulfuric acid, nitric acid, an organic acid, for example.
- the preferred pH is 3-7, more preferably 5-7.
- sodium hydroxide is used as the alkali having a pH of 12 or more and hydrochloric acid is used as the acid having a pH of 7 or less, the salt produced as a by-product is sodium chloride, so that the resulting complex is highly safe.
- curcumin and / or its complex containing a complex of amorphous curcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose A complex of the analog and hydroxypropyl methylcellulose and / or hydroxypropylcellulose can be collected.
- drying step examples include evaporation drying, reduced pressure drying, spray drying, freeze drying, hot air drying, cold air drying, air drying, and the like, preferably vacuum drying, spray drying, and air drying.
- the complex obtained by the method of the present invention has curcumin and / or its analog in an amorphous form, and curcumin and / or its analog has good oral absorbability. It is remarkably superior to the oral absorbability of a mixture of / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose. Therefore, the composition for oral consumption containing the complex is used as a pharmaceutical product, cosmetic product, dietary supplement, functional food product, food for specified health use for exhibiting the physiological activity of curcumin and / or its analogs by oral administration. Useful.
- Reference Example 1 Solubility of curcumin in high pH aqueous solution
- Turmeric extract powder with a curcumin content of 91.2% (w / w) provided by San-Ei Gen FFI was added to 100 mL of an aqueous sodium hydroxide solution adjusted to pH 11, 12, 13 or 14. Gradually added and the curcumin concentration in the aqueous solution at the time when the turmeric extract powder could not be completely dissolved was examined using high performance liquid chromatography (HPLC).
- the curcumin concentration in each aqueous solution is 0.0055 g / 100 mL when dissolved in an aqueous solution of pH 11, 0.111 g / 100 mL when pH 12, 1.42 g / 100 mL when pH 13, and 14 when pH is 14. It was 13.6 g / 100 mL. From this, it was found that a large amount of curcumin can be dissolved in the aqueous solution by using an aqueous solution having a pH value of 12 or more.
- aqueous solution To this aqueous solution was added 2.0 to 8.8 g of turmeric extract powder having a curcumin content of 91.2 or 89.5% (w / w) provided by San-Ei Gen FFI.
- a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose is prepared by adjusting the pH of the aqueous solution to 7 or 6 using a 10 mol / L hydrochloric acid aqueous solution. Prepared.
- the aqueous solution is spray-dried using a spray dryer ADL311S (manufactured by Yamato Scientific Co., Ltd.) under the conditions of an inlet temperature of 160 ° C., an outlet temperature of 75 ° C., a spray pressure of 0.12 MPa, and a feed rate of 6 to 7 mL / min.
- a composite of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose (Examples 1 to 4) was prepared.
- HPMC solution was prepared by dissolving 6 or 12 g of hydroxypropylmethylcellulose (HPMC: Metroles SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) in 150 or 167 mL of pure water.
- HPMC hydroxypropylmethylcellulose
- a sodium hydroxide aqueous solution 50 in which 7.55 or 5.03 g of turmeric extract powder having a curcumin content of 79.5% (w / w) provided by San-Ei Gen F.F.
- a curcumin solution was prepared by dissolving in 33 mL.
- the HPMC solution and the curcumin solution are mixed and the pH of the mixed solution is adjusted to 6 using a 10 mol / L aqueous hydrochloric acid solution to prepare a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose. did.
- 15 or 18 g of dextrin is added here, and the dextrin is dissolved by sufficiently stirring, and then the aqueous solution is spray-dried in the same manner as described above, so that curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose
- the composites (Examples 5 to 6) were prepared.
- a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose was prepared by adjusting the pH of the aqueous solution to 6 using a 10 mol / L hydrochloric acid aqueous solution. Next, the aqueous solution is centrifuged (2,000 ⁇ g, 10 min) to recover the solid content in the aqueous solution, which is placed on a tray and kept in a dark room for about 3 days at room temperature for drying. The dried product was recovered. The dried product was put in a mortar and appropriately pulverized with a pestle to prepare a complex of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose (Example 7). In addition, the case where the composite_body
- Test Example 1 Measurement of Curcumin Crystal in Complex
- the crystallinity of curcumin in the prepared various composites was examined using a powder X-ray diffractometer (RINT-Ultima III, manufactured by Rigaku).
- Test Example 2 (Absorptivity of various amorphous curcumin-containing composites)
- Test animal As test animals, 6-week-old SD rats (male, body weight of about 200 g, Japan Charles River) were used.
- the measurement of plasma curcumin and / or its analog concentration is about 0.5 hour, 1 hour and / or 2 hours after the start of administration, from the jugular vein of the test animal under anesthesia.
- measurement was performed by the following method. a. Pretreatment 100 ⁇ L of 0.1 M acetate buffer (pH 5.0) and 10 ⁇ L of ⁇ -glucuronidase solution (about 68,000 units / mL) were added to 20 ⁇ L of the collected plasma and held at 37 ° C. for 1 hour.
- curcumin concentration 0 prepared by adding 10 ⁇ L of 50% ethanol solution containing 20 ng / mL mepronil to 90 ⁇ L of 50% (v / v) methanol solution (curcumin standard solution) containing 5, 125 or 250 ng / mL 9 to 225 ng / mL) under the same conditions as described above.
- Table 4 shows the curcumin concentration in plasma (ng / mL), the maximum blood concentration (Cmax (ng / mL)), and the area under the blood concentration-time curve (AUC (ng / mL ⁇ 0-2hr)). . It can be seen that the oral absorbability of the complex obtained by the present invention is remarkably improved as compared with the curcumin bulk powder and the physical mixture.
Abstract
Provided is a method for easily producing a composite that contains amorphous curcumin and/or an analogue thereof in high concentration at low cost, said composite having a high content of curcumin and/or an analogue thereof and improved absorption of curcumin and/or an analogue thereof in the body by oral intake.
A method for producing a composite of curcumin and/or an analogue thereof and hydroxypropyl methylcellulose and/or hydroxypropyl cellulose, said composite containing amorphous curcumin and/or an analogue thereof, which is characterized by comprising: a step for dissolving curcumin and/or an analogue thereof and hydroxypropyl methylcellulose and/or hydroxypropyl cellulose into an aqueous solution having a pH of 12 or more; and a step for decreasing the pH of the solution to 7 or less.
Description
本発明は、非晶質クルクミン及び／又はその類縁体を含有する複合体の製造方法に関する。
The present invention relates to a method for producing a complex containing amorphous curcumin and / or an analog thereof.
クルクミン及びその類縁体は、近年、腫瘍形成阻害作用、抗酸化作用、抗炎症作用、コレステロール低下作用、抗アレルギー作用、脳疾患予防作用、心疾患予防治療作用等の生理活性を有することが明らかとなり、食品（例えば、機能性食品など）、医薬品や化粧品等への利用が検討されている。しかし、クルクミン及びその類縁体は、経口摂取による体内への吸収性が著しく低いため、クルクミン及びその類縁体がもつ生理活性が経口摂取によって十分に得られないといった問題がある。
In recent years, it has become clear that curcumin and its analogs have physiological activities such as tumor formation inhibitory action, antioxidant action, anti-inflammatory action, cholesterol lowering action, antiallergic action, brain disease prevention action, and heart disease prevention and treatment action. Application to foods (for example, functional foods), pharmaceuticals, cosmetics, and the like has been studied. However, curcumin and its analogs have a problem that the physiological activity of curcumin and its analogs cannot be sufficiently obtained by oral ingestion because their absorption into the body is extremely low.
そこで、クルクミン及びその類縁体の吸収性を改善する方法の一つとして、特許文献１には、クルクミノイドと、熱可塑性ポリマーと、ホスファチドを溶融加工することによってクルクミノイドを非晶質化させ、該クルクミノイド製剤を経口摂取することでクルクミノイドの体内への吸収性を向上させる方法が開示されている。
一方、クルクミンとポリサッカロイドとの複合体を製造する方法の一つとして、特許文献２には、クルクミンと水溶性で分枝鎖のある若しくは環状のポリサッカライド（変性した食用デンプン、ペクチン、植物ゴム、アルギン酸プロピレングリコール、シクロデキストリン、アミロペクチン由来のマルトデキストリン及びカルボキシメチルセルロース）とをｐＨ約９以上の水溶液中で接触させ、ｐＨ約８以下になるように酸性化させるクルクミン複合体の製造方法が開示されている。 Thus, as one method for improving the absorbability of curcumin and its analogs, Patent Document 1 discloses that curcuminoids are made amorphous by melt-processing curcuminoids, thermoplastic polymers, and phosphatides, and the curcuminoids are made amorphous. A method for improving the absorption of curcuminoids into the body by ingesting the preparation is disclosed.
On the other hand, as one method for producing a complex of curcumin and polysaccharide, Patent Document 2 discloses a water-soluble, branched or cyclic polysaccharide (modified edible starch, pectin, plant). A method for producing a curcumin complex is disclosed in which rubber, propylene glycol alginate, cyclodextrin, maltodextrin derived from amylopectin and carboxymethylcellulose) are contacted in an aqueous solution having a pH of about 9 or more and acidified to have a pH of about 8 or less. Has been.
一方、クルクミンとポリサッカロイドとの複合体を製造する方法の一つとして、特許文献２には、クルクミンと水溶性で分枝鎖のある若しくは環状のポリサッカライド（変性した食用デンプン、ペクチン、植物ゴム、アルギン酸プロピレングリコール、シクロデキストリン、アミロペクチン由来のマルトデキストリン及びカルボキシメチルセルロース）とをｐＨ約９以上の水溶液中で接触させ、ｐＨ約８以下になるように酸性化させるクルクミン複合体の製造方法が開示されている。 Thus, as one method for improving the absorbability of curcumin and its analogs, Patent Document 1 discloses that curcuminoids are made amorphous by melt-processing curcuminoids, thermoplastic polymers, and phosphatides, and the curcuminoids are made amorphous. A method for improving the absorption of curcuminoids into the body by ingesting the preparation is disclosed.
On the other hand, as one method for producing a complex of curcumin and polysaccharide, Patent Document 2 discloses a water-soluble, branched or cyclic polysaccharide (modified edible starch, pectin, plant). A method for producing a curcumin complex is disclosed in which rubber, propylene glycol alginate, cyclodextrin, maltodextrin derived from amylopectin and carboxymethylcellulose) are contacted in an aqueous solution having a pH of about 9 or more and acidified to have a pH of about 8 or less. Has been.
しかしながら、特許文献１記載の溶融加工は、加熱後溶融物をノズルを通して固体分散体を得る必要があり、特殊な技術や装置が必要であることや製造コストが高いことなどの問題がある。一方、特許文献２で得られたクルクミン複合体は、食品の着色剤として利用されるものであり、経口摂取によるクルクミン及び／又はその類縁体の体内への吸収性を向上させる目的で利用されるものではない。また、当該複合体が非晶質であることは示されていない。
However, the melt processing described in Patent Document 1 has a problem in that it is necessary to obtain a solid dispersion through a nozzle after heating and a special technique and apparatus are required and the manufacturing cost is high. On the other hand, the curcumin complex obtained in Patent Document 2 is used as a colorant for foods, and is used for the purpose of improving the absorption of curcumin and / or its analogs by ingestion into the body. It is not a thing. Further, it is not shown that the complex is amorphous.
従って、本発明の課題は、クルクミン及び／又はその類縁体の含量が高く、かつ、簡便で安価に、経口摂取によりクルクミン及び／又はその類縁体の体内への吸収性を向上した非晶質クルクミン及び／又はその類縁体を含有する複合体を高濃度で製造する方法を提供することにある。
Accordingly, an object of the present invention is to provide an amorphous curcumin having a high content of curcumin and / or an analog thereof, and improving the absorption of curcumin and / or an analog thereof into the body by oral ingestion at low cost. And / or providing a method for producing a complex containing the analog at a high concentration.
そこで本発明者は、経口摂取による体内への吸収性を向上させるクルクミン及び／又はその類縁体について鋭意検討を重ねたところ、クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの両者をｐＨ１２以上の水溶液に溶解させた後、該溶液のｐＨを７以下にすれば、経口摂取により体内への吸収性が顕著に改善された非晶質クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの複合体が得られることを見出し、本発明を完成した。
Therefore, the present inventor has conducted extensive studies on curcumin and / or its analogs that improve absorption into the body by oral ingestion. As a result, curcumin and / or its analogs and hydroxypropylmethylcellulose and / or hydroxypropylcellulose After dissolving both of these in an aqueous solution having a pH of 12 or more, the pH of the solution is adjusted to 7 or less. Amorphous curcumin and / or its analogs and hydroxy having significantly improved absorption in the body by oral ingestion. It discovered that the composite_body | complex with propylmethylcellulose and / or hydroxypropylcellulose was obtained, and completed this invention.
すなわち、本発明は、次の〔１〕～〔５〕を提供するものである。
That is, the present invention provides the following [1] to [5].
〔１〕クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとをｐＨ１２以上の水溶液に溶解させる工程と、該溶液のｐＨを７以下にする工程と、を有することを特徴とする、非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔２〕さらに、前記ｐＨ７以下とした溶液から水分を取り除く乾燥工程を有する、〔１〕に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔３〕前記類縁体が、ビスデメトキシクルクミン、デメトキシクルクミン及びテトラヒドロクルクミンからなる群から選択された少なくとも１種である、〔１〕又は〔２〕に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔４〕前記クルクミン及び／又はその類縁体（Ａ）と前記ヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロース（Ｂ）との含有比率（Ａ／Ｂ）が、０．１～１０である、〔１〕～〔３〕のいずれかに記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔５〕前記乾燥工程が、噴霧乾燥、減圧乾燥又は風乾である〔１〕～〔４〕のいずれかに記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 [1] It comprises a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more, and a step of adjusting the pH of the solution to 7 or less. A method for producing a complex of curcumin containing amorphous curcumin and / or an analog thereof and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[2] Curcumin and / or its analog and hydroxypropylmethylcellulose containing amorphous curcumin and / or its analog according to [1], further comprising a drying step for removing water from the solution having a pH of 7 or less And / or a method for producing a complex with hydroxypropylcellulose.
[3] The amorphous curcumin according to [1] or [2] and / or the analog curcumin is at least one selected from the group consisting of bisdemethoxycurcumin, demethoxycurcumin and tetrahydrocurcumin A method for producing a complex of curcumin containing an analog and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[4] The content ratio (A / B) of the curcumin and / or its analog (A) to the hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0.1 to 10. [1] A method for producing a complex of curcumin and / or an analog thereof containing the amorphous curcumin and / or an analog thereof according to any one of [3] to [3] and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[5] Curcumin and / or its analogs containing amorphous curcumin and / or its analogs according to any one of [1] to [4], wherein the drying step is spray drying, vacuum drying or air drying For producing a composite of hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
〔２〕さらに、前記ｐＨ７以下とした溶液から水分を取り除く乾燥工程を有する、〔１〕に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔３〕前記類縁体が、ビスデメトキシクルクミン、デメトキシクルクミン及びテトラヒドロクルクミンからなる群から選択された少なくとも１種である、〔１〕又は〔２〕に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔４〕前記クルクミン及び／又はその類縁体（Ａ）と前記ヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロース（Ｂ）との含有比率（Ａ／Ｂ）が、０．１～１０である、〔１〕～〔３〕のいずれかに記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。
〔５〕前記乾燥工程が、噴霧乾燥、減圧乾燥又は風乾である〔１〕～〔４〕のいずれかに記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 [1] It comprises a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more, and a step of adjusting the pH of the solution to 7 or less. A method for producing a complex of curcumin containing amorphous curcumin and / or an analog thereof and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[2] Curcumin and / or its analog and hydroxypropylmethylcellulose containing amorphous curcumin and / or its analog according to [1], further comprising a drying step for removing water from the solution having a pH of 7 or less And / or a method for producing a complex with hydroxypropylcellulose.
[3] The amorphous curcumin according to [1] or [2] and / or the analog curcumin is at least one selected from the group consisting of bisdemethoxycurcumin, demethoxycurcumin and tetrahydrocurcumin A method for producing a complex of curcumin containing an analog and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[4] The content ratio (A / B) of the curcumin and / or its analog (A) to the hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0.1 to 10. [1] A method for producing a complex of curcumin and / or an analog thereof containing the amorphous curcumin and / or an analog thereof according to any one of [3] to [3] and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
[5] Curcumin and / or its analogs containing amorphous curcumin and / or its analogs according to any one of [1] to [4], wherein the drying step is spray drying, vacuum drying or air drying For producing a composite of hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
本発明の製造方法によれば、クルクミン及び／又はその類縁体の含量が高く、かつ、非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体を特殊な技術や装置を必要とせず、簡便で安価に、高濃度で製造することができる。
また、本発明の製造方法によって調製した非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体は、該複合体を経口摂取することによって、体内へのクルクミン及び／又はその類縁体の吸収性を改善することができる。 According to the production method of the present invention, the content of curcumin and / or its analog is high, and curcumin and / or its analog and hydroxypropylmethylcellulose containing amorphous curcumin and / or its analog and / or A complex with hydroxypropylcellulose can be produced at a high concentration in a simple and inexpensive manner without the need for special techniques or equipment.
In addition, a complex of curcumin and / or an analog thereof containing amorphous curcumin and / or an analog thereof prepared by the production method of the present invention is hydroxypropylmethylcellulose and / or hydroxypropylcellulose. By taking orally, the absorption of curcumin and / or its analogs into the body can be improved.
また、本発明の製造方法によって調製した非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体は、該複合体を経口摂取することによって、体内へのクルクミン及び／又はその類縁体の吸収性を改善することができる。 According to the production method of the present invention, the content of curcumin and / or its analog is high, and curcumin and / or its analog and hydroxypropylmethylcellulose containing amorphous curcumin and / or its analog and / or A complex with hydroxypropylcellulose can be produced at a high concentration in a simple and inexpensive manner without the need for special techniques or equipment.
In addition, a complex of curcumin and / or an analog thereof containing amorphous curcumin and / or an analog thereof prepared by the production method of the present invention is hydroxypropylmethylcellulose and / or hydroxypropylcellulose. By taking orally, the absorption of curcumin and / or its analogs into the body can be improved.
本発明の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法は、
（１）クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとをｐＨ１２以上の水溶液に溶解させる工程と、
（２）該溶液のｐＨを７以下にする工程と、を有することを特徴とする。 A method for producing a complex of curcumin and / or its analog containing hydroxycurcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose containing the amorphous curcumin of the present invention and / or its analog,
(1) a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more;
(2) The step of adjusting the pH of the solution to 7 or less.
（１）クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとをｐＨ１２以上の水溶液に溶解させる工程と、
（２）該溶液のｐＨを７以下にする工程と、を有することを特徴とする。 A method for producing a complex of curcumin and / or its analog containing hydroxycurcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose containing the amorphous curcumin of the present invention and / or its analog,
(1) a step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more;
(2) The step of adjusting the pH of the solution to 7 or less.
クルクミンは、ウコン色素に含まれるクルクミノイドの主成分であり、下記構造式（１）で表される化合物である。
Curcumin is a main component of curcuminoid contained in the turmeric pigment, and is a compound represented by the following structural formula (1).
本発明に用いられるクルクミンは、化学合成されたクルクミンを用いてもよいし、ウコン色素として流通しているものを用いてもよい。ウコン色素としては、ショウガ科ウコン属植物（例えば、Curcuma longa LINNE）の根茎の乾燥物を粉末にしたウコン末、該ウコン末を適当な溶媒（例えば、エタノール、油脂、プロピレングリコール、ヘキサン、アセトンなど）を用いて抽出して得られる粗製クルクミン或いはオレオレジン（ターメリックオレオレジン）、および精製したクルクミンを挙げることができる。
なお、クルクミンには、互変異性体であるケト型及びエノール型のいずれも含まれる。 Curcumin used in the present invention may be chemically synthesized curcumin, or may be one that is distributed as a turmeric pigment. As the turmeric pigment, turmeric powder obtained by powdering dried rhizomes of ginger family turmeric (for example, Curcuma longa LINNE), the turmeric powder with an appropriate solvent (for example, ethanol, fat, propylene glycol, hexane, acetone, etc.) ), And crude curcumin or oleoresin (turmeric oleoresin) obtained by extraction with the use of) and purified curcumin.
Curcumin includes both tautomeric keto type and enol type.
なお、クルクミンには、互変異性体であるケト型及びエノール型のいずれも含まれる。 Curcumin used in the present invention may be chemically synthesized curcumin, or may be one that is distributed as a turmeric pigment. As the turmeric pigment, turmeric powder obtained by powdering dried rhizomes of ginger family turmeric (for example, Curcuma longa LINNE), the turmeric powder with an appropriate solvent (for example, ethanol, fat, propylene glycol, hexane, acetone, etc.) ), And crude curcumin or oleoresin (turmeric oleoresin) obtained by extraction with the use of) and purified curcumin.
Curcumin includes both tautomeric keto type and enol type.
クルクミン類縁体としては、デメトキシクルクミン、ビスデメトキシクルクミン、テトラヒドロクルクミン、ジヒドロキシテトラヒドロクルクミン等が挙げられる。なお、ウコン色素には、クルクミン、デメトキシクルクミン、ビスデメトキシクルクミン及びテトラヒドロクルクミンが含まれている。
Examples of curcumin analogs include demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin, dihydroxytetrahydrocurcumin and the like. The turmeric pigments include curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin.
ヒドロキシプロピルメチルセルロースは、セルロースのヒドロキシ基の一部がメトキシ基及びヒドロキシプロピルオキシ基に置換した水溶性セルロース誘導体である。メトキシ基及びヒドロキシプロピルオキシ基の置換度は種々のものが知られており、食品として使用可能なものがいずれも使用できる。ヒドロキシプロピルセルロースは、セルロースのヒドロキシ基の一部がヒドロキシプロピルオキシ基に置換した水溶性セルロース誘導体である。ヒドロキシプロピルオキシ基の置換度は種々のものが知られており、食品として使用可能なものがいずれも使用できる。
Hydroxypropyl methylcellulose is a water-soluble cellulose derivative in which part of the hydroxy group of cellulose is substituted with a methoxy group and a hydroxypropyloxy group. Various substitution degrees of the methoxy group and the hydroxypropyloxy group are known, and any of those usable as food can be used. Hydroxypropyl cellulose is a water-soluble cellulose derivative in which part of the hydroxy group of cellulose is substituted with a hydroxypropyloxy group. Various substitution degrees of hydroxypropyloxy groups are known, and any of those usable as food can be used.
クルクミン及び／又はその類縁体（Ａ）とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロース（Ｂ）との使用質量比率（Ａ／Ｂ）は、優れた経口吸収性を有する複合体を得る点から、０．０２～１０が好ましく、０．０３～１０がより好ましく、０．０５～１０がさらに好ましく、０．１～１０がさらに好ましい。また、得られる複合体中の含有質量比率（Ａ／Ｂ）は、使用質量比率（Ａ／Ｂ）と同一である。
The mass ratio (A / B) of curcumin and / or its analog (A) and hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0 from the point of obtaining a complex having excellent oral absorbability. 0.02 to 10, preferably 0.03 to 10, more preferably 0.05 to 10, and still more preferably 0.1 to 10. Moreover, the containing mass ratio (A / B) in the obtained composite_body | complex is the same as a use mass ratio (A / B).
ｐＨ１２以上の水溶液としては、水酸化ナトリウム、水酸化カリウム等のアルカリ水溶液が挙げられる。このうち、水酸化ナトリウム水溶液が特に好ましい。また、ｐＨは１２以上であればよいが、ｐＨ１２～１５が好ましく、ｐＨ１２～１４がさらに好ましい。
Examples of aqueous solutions having a pH of 12 or higher include alkaline aqueous solutions such as sodium hydroxide and potassium hydroxide. Of these, an aqueous sodium hydroxide solution is particularly preferred. The pH may be 12 or more, but is preferably pH 12 to 15, more preferably pH 12 to 14.
ｐＨ１２以上の水溶液へのクルクミン及び／又はその類縁体の添加量は、飽和濃度になる量が好ましく、０．１ｇ／１００ｍＬ以上が好ましく、０．１～１０ｇ／１００ｍＬがより好ましい。
The amount of curcumin and / or its analog added to an aqueous solution having a pH of 12 or higher is preferably such that it reaches a saturated concentration, preferably 0.1 g / 100 mL or more, and more preferably 0.1 to 10 g / 100 mL.
本発明方法の工程（１）においては、クルクミン及び／又はその類縁体（Ａ）と（Ｂ）ヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとをｐＨ１２以上の水溶液に溶解させればよく、例えば、水に（Ａ）と（Ｂ）を添加後にｐＨを１２以上に調整してもよく、ｐＨ１２以上の水溶液に（Ａ）と（Ｂ）とを添加して溶解させてもよく、（Ｂ）の水溶液をｐＨ１２以上に調整後（Ａ）を添加してもよく、（Ａ）の水分散液をｐＨ１２以上に調整後（Ｂ）を添加してもよい。
In step (1) of the method of the present invention, curcumin and / or its analog (A) and (B) hydroxypropylmethylcellulose and / or hydroxypropylcellulose may be dissolved in an aqueous solution having a pH of 12 or more. After adding (A) and (B), the pH may be adjusted to 12 or more, and (A) and (B) may be added and dissolved in an aqueous solution having a pH of 12 or more. (A) may be added after adjusting the pH to 12 or higher, and (B) may be added after adjusting the aqueous dispersion of (A) to pH 12 or higher.
次に、前記溶液のｐＨを７以下に調整する。ｐＨを７以下にするには、例えば塩酸、硫酸、硝酸、有機酸等の酸を添加するのが好ましい。好ましいｐＨは、３～７であり、５～７がより好ましい。ｐＨ１２以上とするアルカリとして水酸化ナトリウムを使用し、ｐＨ７以下とする酸として塩酸を使用した場合、副生する塩が塩化ナトリウムなので、得られる複合体の安全性が高い。
Next, the pH of the solution is adjusted to 7 or less. In order to make pH 7 or less, it is preferable to add acids, such as hydrochloric acid, a sulfuric acid, nitric acid, an organic acid, for example. The preferred pH is 3-7, more preferably 5-7. When sodium hydroxide is used as the alkali having a pH of 12 or more and hydrochloric acid is used as the acid having a pH of 7 or less, the salt produced as a by-product is sodium chloride, so that the resulting complex is highly safe.
ｐＨを７以下にすることにより、非晶質クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの複合体が生成し、析出する。
When the pH is adjusted to 7 or less, a complex of amorphous curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose is generated and precipitated.
次に、ｐＨ７以下とした溶液から水分を取り除く乾燥工程を行えば、非晶質クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの複合体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの複合体が採取できる。
Next, if a drying step for removing water from the solution having a pH of 7 or less is performed, curcumin and / or its complex containing a complex of amorphous curcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose A complex of the analog and hydroxypropyl methylcellulose and / or hydroxypropylcellulose can be collected.
乾燥工程としては、蒸発乾燥、減圧乾燥、噴霧乾燥、凍結乾燥、温風乾燥、冷風乾燥、風乾等が挙げられるが、減圧乾燥、噴霧乾燥及び風乾が好ましい。
Examples of the drying step include evaporation drying, reduced pressure drying, spray drying, freeze drying, hot air drying, cold air drying, air drying, and the like, preferably vacuum drying, spray drying, and air drying.
本発明方法により得られる複合体は、クルクミン及び／又はその類縁体が非晶質の形態であり、クルクミン及び／又はその類縁体の経口吸収性が良好であり、その経口吸収性は、クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースとの混合物の経口吸収性に比べて顕著に優れている。従って、当該複合体を含有する経口摂取用組成物は、クルクミン及び／又はその類縁体の生理活性を経口投与で発揮させるための医薬品、化粧品、栄養補助食品、機能性食品、特定保健用食品として有用である。
The complex obtained by the method of the present invention has curcumin and / or its analog in an amorphous form, and curcumin and / or its analog has good oral absorbability. It is remarkably superior to the oral absorbability of a mixture of / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose. Therefore, the composition for oral consumption containing the complex is used as a pharmaceutical product, cosmetic product, dietary supplement, functional food product, food for specified health use for exhibiting the physiological activity of curcumin and / or its analogs by oral administration. Useful.
次に実施例を挙げて本発明をさらに詳細に説明する。
Next, the present invention will be described in more detail with reference to examples.
１．参考例１（高ｐＨ水溶液におけるクルクミンの溶解性）
ｐＨを１１、１２、１３又は１４に調整した水酸化ナトリウム水溶液１００ｍＬに、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２％（ｗ／ｗ）のウコン抽出物粉末を徐々に添加し、該ウコン抽出物粉末が溶けきれなくなる時点での該水溶液中のクルクミン濃度を高速液体クロマトグラフィー（ＨＰＬＣ）を用いて調べた。なお、この時のＨＰＬＣ分析条件は、試料量が１０μＬ、カラムがＡｔｌａｎｔｉｓ Ｔ３（２．１×１５０ｍｍ，３μｍ，Ｗａｔｅｒｓ社製）、カラム温度が４０℃、流速が０．２ｍＬ／ｍｉｎ、移動相がＡ：０．１％ギ酸水溶液、Ｂ：０．１％ギ酸／アセトニトリルとし、Ａ：Ｂ＝４０：６０の溶液を用いて溶出を行った。
その結果、各水溶液中のクルクミン濃度は、ｐＨ１１の水溶液に溶解させた場合では０．００５５ｇ／１００ｍＬ、ｐＨ１２の場合では０．１１１ｇ／１００ｍＬ、ｐＨ１３の場合では１．４２ｇ／１００ｍＬ、ｐＨ１４の場合では１３．６ｇ／１００ｍＬであった。このことから、ｐＨ値が１２以上の水溶液を用いることによって多量のクルクミンを水溶液中に溶解させることができることが分かった。 1. Reference Example 1 (Solubility of curcumin in high pH aqueous solution)
Turmeric extract powder with a curcumin content of 91.2% (w / w) provided by San-Ei Gen FFI was added to 100 mL of an aqueous sodium hydroxide solution adjusted topH 11, 12, 13 or 14. Gradually added and the curcumin concentration in the aqueous solution at the time when the turmeric extract powder could not be completely dissolved was examined using high performance liquid chromatography (HPLC). The HPLC analysis conditions at this time were as follows: the sample amount was 10 μL, the column was Atlantis T3 (2.1 × 150 mm, 3 μm, manufactured by Waters), the column temperature was 40 ° C., the flow rate was 0.2 mL / min, and the mobile phase was Elution was performed using A: 0.1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile, and a solution of A: B = 40: 60.
As a result, the curcumin concentration in each aqueous solution is 0.0055 g / 100 mL when dissolved in an aqueous solution ofpH 11, 0.111 g / 100 mL when pH 12, 1.42 g / 100 mL when pH 13, and 14 when pH is 14. It was 13.6 g / 100 mL. From this, it was found that a large amount of curcumin can be dissolved in the aqueous solution by using an aqueous solution having a pH value of 12 or more.
ｐＨを１１、１２、１３又は１４に調整した水酸化ナトリウム水溶液１００ｍＬに、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２％（ｗ／ｗ）のウコン抽出物粉末を徐々に添加し、該ウコン抽出物粉末が溶けきれなくなる時点での該水溶液中のクルクミン濃度を高速液体クロマトグラフィー（ＨＰＬＣ）を用いて調べた。なお、この時のＨＰＬＣ分析条件は、試料量が１０μＬ、カラムがＡｔｌａｎｔｉｓ Ｔ３（２．１×１５０ｍｍ，３μｍ，Ｗａｔｅｒｓ社製）、カラム温度が４０℃、流速が０．２ｍＬ／ｍｉｎ、移動相がＡ：０．１％ギ酸水溶液、Ｂ：０．１％ギ酸／アセトニトリルとし、Ａ：Ｂ＝４０：６０の溶液を用いて溶出を行った。
その結果、各水溶液中のクルクミン濃度は、ｐＨ１１の水溶液に溶解させた場合では０．００５５ｇ／１００ｍＬ、ｐＨ１２の場合では０．１１１ｇ／１００ｍＬ、ｐＨ１３の場合では１．４２ｇ／１００ｍＬ、ｐＨ１４の場合では１３．６ｇ／１００ｍＬであった。このことから、ｐＨ値が１２以上の水溶液を用いることによって多量のクルクミンを水溶液中に溶解させることができることが分かった。 1. Reference Example 1 (Solubility of curcumin in high pH aqueous solution)
Turmeric extract powder with a curcumin content of 91.2% (w / w) provided by San-Ei Gen FFI was added to 100 mL of an aqueous sodium hydroxide solution adjusted to
As a result, the curcumin concentration in each aqueous solution is 0.0055 g / 100 mL when dissolved in an aqueous solution of
実施例１～７（非晶質クルクミン含有複合体の調製）
（１）調製方法Ａ－１（スプレードライ（ＳＤ）による乾燥）
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）又はヒドロキシプロピルセルロース（ＨＰＣ：ＳＳＬ、日本曹達社製）２．０～８．０ｇを純水２００～８００ｍＬに溶解させた後、１０ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いて該水溶液のｐＨを１３に調整した。この水溶液に、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２又は８９．５％（ｗ／ｗ）のウコン抽出物粉末２．０～８．８ｇを添加し、よく撹拌することで溶解させた後、１０ｍｏｌ／Ｌ塩酸水溶液を用いて該水溶液のｐＨを７又は６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとの複合体を調製した。
次いで、該水溶液をスプレードライヤＡＤＬ３１１Ｓ（ヤマト科学株式会社製）を用いて、ｉｎｌｅｔ ｔｅｍｐｅｒａｔｕｒｅ １６０℃、ｏｕｔｌｅｔ ｔｅｍｐｅｒａｔｕｒｅ ７５℃、ｓｐｒａｙ ｐｒｅｓｓｕｒｅ ０．１２ＭＰａ、ｆｅｅｄ ｒａｔｅ ６～７ｍＬ／ｍｉｎの条件で噴霧乾燥することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとの複合体（実施例１～４）を調製した。 Examples 1 to 7 (Preparation of amorphous curcumin-containing composite)
(1) Preparation method A-1 (Drying by spray drying (SD))
After dissolving 2.0-8.0 g of hydroxypropylmethylcellulose (HPMC: Metroles SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) or hydroxypropylcellulose (HPC: SSL, manufactured by Nippon Soda Co., Ltd.) in 200-800 mL of pure water, The pH of the aqueous solution was adjusted to 13 using a 10 mol / L aqueous sodium hydroxide solution. To this aqueous solution was added 2.0 to 8.8 g of turmeric extract powder having a curcumin content of 91.2 or 89.5% (w / w) provided by San-Ei Gen FFI. After dissolving by stirring, a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose is prepared by adjusting the pH of the aqueous solution to 7 or 6 using a 10 mol / L hydrochloric acid aqueous solution. Prepared.
Next, the aqueous solution is spray-dried using a spray dryer ADL311S (manufactured by Yamato Scientific Co., Ltd.) under the conditions of an inlet temperature of 160 ° C., an outlet temperature of 75 ° C., a spray pressure of 0.12 MPa, and a feed rate of 6 to 7 mL / min. A composite of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose (Examples 1 to 4) was prepared.
（１）調製方法Ａ－１（スプレードライ（ＳＤ）による乾燥）
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）又はヒドロキシプロピルセルロース（ＨＰＣ：ＳＳＬ、日本曹達社製）２．０～８．０ｇを純水２００～８００ｍＬに溶解させた後、１０ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いて該水溶液のｐＨを１３に調整した。この水溶液に、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２又は８９．５％（ｗ／ｗ）のウコン抽出物粉末２．０～８．８ｇを添加し、よく撹拌することで溶解させた後、１０ｍｏｌ／Ｌ塩酸水溶液を用いて該水溶液のｐＨを７又は６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとの複合体を調製した。
次いで、該水溶液をスプレードライヤＡＤＬ３１１Ｓ（ヤマト科学株式会社製）を用いて、ｉｎｌｅｔ ｔｅｍｐｅｒａｔｕｒｅ １６０℃、ｏｕｔｌｅｔ ｔｅｍｐｅｒａｔｕｒｅ ７５℃、ｓｐｒａｙ ｐｒｅｓｓｕｒｅ ０．１２ＭＰａ、ｆｅｅｄ ｒａｔｅ ６～７ｍＬ／ｍｉｎの条件で噴霧乾燥することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとの複合体（実施例１～４）を調製した。 Examples 1 to 7 (Preparation of amorphous curcumin-containing composite)
(1) Preparation method A-1 (Drying by spray drying (SD))
After dissolving 2.0-8.0 g of hydroxypropylmethylcellulose (HPMC: Metroles SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) or hydroxypropylcellulose (HPC: SSL, manufactured by Nippon Soda Co., Ltd.) in 200-800 mL of pure water, The pH of the aqueous solution was adjusted to 13 using a 10 mol / L aqueous sodium hydroxide solution. To this aqueous solution was added 2.0 to 8.8 g of turmeric extract powder having a curcumin content of 91.2 or 89.5% (w / w) provided by San-Ei Gen FFI. After dissolving by stirring, a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose is prepared by adjusting the pH of the aqueous solution to 7 or 6 using a 10 mol / L hydrochloric acid aqueous solution. Prepared.
Next, the aqueous solution is spray-dried using a spray dryer ADL311S (manufactured by Yamato Scientific Co., Ltd.) under the conditions of an inlet temperature of 160 ° C., an outlet temperature of 75 ° C., a spray pressure of 0.12 MPa, and a feed rate of 6 to 7 mL / min. A composite of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose or hydroxypropylcellulose (Examples 1 to 4) was prepared.
（２）調製方法Ａ－２
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）６又は１２ｇを純水１５０又は１６７ｍＬに溶解させてＨＰＭＣ溶液を調製した。一方、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が７９．５％（ｗ／ｗ）のウコン抽出物粉末７．５５又は５．０３ｇをｐＨ１４に調整した水酸化ナトリウム水溶液５０又は３３ｍＬに溶解させてクルクミン溶液を調製した。その後、上記ＨＰＭＣ溶液とクルクミン溶液とを混合し、該混合溶液のｐＨを１０ｍｏｌ／Ｌ塩酸水溶液を用いて６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した。
また、ここにデキストリン１５又は１８ｇを添加して十分撹拌することで該デキストリンを溶解させた後、該水溶液を上記と同様に噴霧乾燥することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースの複合体（実施例５～６）を調製した。 (2) Preparation method A-2
A HPMC solution was prepared by dissolving 6 or 12 g of hydroxypropylmethylcellulose (HPMC: Metroles SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) in 150 or 167 mL of pure water. On the other hand, a sodium hydroxide aqueous solution 50 in which 7.55 or 5.03 g of turmeric extract powder having a curcumin content of 79.5% (w / w) provided by San-Ei Gen F.F. A curcumin solution was prepared by dissolving in 33 mL. Thereafter, the HPMC solution and the curcumin solution are mixed and the pH of the mixed solution is adjusted to 6 using a 10 mol / L aqueous hydrochloric acid solution to prepare a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose. did.
In addition, 15 or 18 g of dextrin is added here, and the dextrin is dissolved by sufficiently stirring, and then the aqueous solution is spray-dried in the same manner as described above, so that curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose The composites (Examples 5 to 6) were prepared.
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）６又は１２ｇを純水１５０又は１６７ｍＬに溶解させてＨＰＭＣ溶液を調製した。一方、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が７９．５％（ｗ／ｗ）のウコン抽出物粉末７．５５又は５．０３ｇをｐＨ１４に調整した水酸化ナトリウム水溶液５０又は３３ｍＬに溶解させてクルクミン溶液を調製した。その後、上記ＨＰＭＣ溶液とクルクミン溶液とを混合し、該混合溶液のｐＨを１０ｍｏｌ／Ｌ塩酸水溶液を用いて６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した。
また、ここにデキストリン１５又は１８ｇを添加して十分撹拌することで該デキストリンを溶解させた後、該水溶液を上記と同様に噴霧乾燥することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースの複合体（実施例５～６）を調製した。 (2) Preparation method A-2
A HPMC solution was prepared by dissolving 6 or 12 g of hydroxypropylmethylcellulose (HPMC: Metroles SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) in 150 or 167 mL of pure water. On the other hand, a sodium hydroxide aqueous solution 50 in which 7.55 or 5.03 g of turmeric extract powder having a curcumin content of 79.5% (w / w) provided by San-Ei Gen F.F. A curcumin solution was prepared by dissolving in 33 mL. Thereafter, the HPMC solution and the curcumin solution are mixed and the pH of the mixed solution is adjusted to 6 using a 10 mol / L aqueous hydrochloric acid solution to prepare a complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose. did.
In addition, 15 or 18 g of dextrin is added here, and the dextrin is dissolved by sufficiently stirring, and then the aqueous solution is spray-dried in the same manner as described above, so that curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose The composites (Examples 5 to 6) were prepared.
（３）調製方法Ｂ（風乾による乾燥）
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）２．０ｇを純水２００ｍＬに溶解させた後、１０ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いて該水溶液のｐＨを１３に調整した。この水溶液に、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２％（ｗ／ｗ）のウコン抽出物粉末２．２ｇを添加し、よく撹拌することで溶解させた後、１０ｍｏｌ／Ｌ塩酸水溶液を用いて該水溶液のｐＨを６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した。
次いで、該水溶液を遠心分離（２，０００×ｇ、１０ｍｉｎ）することで該水溶液中の固形分を回収し、これをトレーにのせて暗室内で約３日間、室温で保持することで乾燥させ、該乾燥物を回収した。また、該乾燥物を乳鉢に入れて乳棒で適宜粉砕することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した（実施例７）。
なお、水溶性セルロース誘導体であるヒドロキシプロピルメチルセルロースの代わりにメチルセルロースを用いて複合体を調製した場合を比較例１とした。 (3) Preparation method B (drying by air drying)
After 2.0 g of hydroxypropylmethylcellulose (HPMC: Metrolose SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in 200 mL of pure water, the pH of the aqueous solution was adjusted to 13 using a 10 mol / L sodium hydroxide aqueous solution. After adding 2.2 g of turmeric extract powder having a curcumin content of 91.2% (w / w) provided by San-Ei Gen FFI Co., Ltd. A complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose was prepared by adjusting the pH of the aqueous solution to 6 using a 10 mol / L hydrochloric acid aqueous solution.
Next, the aqueous solution is centrifuged (2,000 × g, 10 min) to recover the solid content in the aqueous solution, which is placed on a tray and kept in a dark room for about 3 days at room temperature for drying. The dried product was recovered. The dried product was put in a mortar and appropriately pulverized with a pestle to prepare a complex of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose (Example 7).
In addition, the case where the composite_body | complex was prepared using methylcellulose instead of the hydroxypropyl methylcellulose which is a water-soluble cellulose derivative was made into the comparative example 1.
ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：メトローズＳＥ－０６、信越化学工業社製）２．０ｇを純水２００ｍＬに溶解させた後、１０ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いて該水溶液のｐＨを１３に調整した。この水溶液に、三栄源エフ・エフ・アイ社から供与されたクルクミン含有量が９１．２％（ｗ／ｗ）のウコン抽出物粉末２．２ｇを添加し、よく撹拌することで溶解させた後、１０ｍｏｌ／Ｌ塩酸水溶液を用いて該水溶液のｐＨを６に調整することで非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した。
次いで、該水溶液を遠心分離（２，０００×ｇ、１０ｍｉｎ）することで該水溶液中の固形分を回収し、これをトレーにのせて暗室内で約３日間、室温で保持することで乾燥させ、該乾燥物を回収した。また、該乾燥物を乳鉢に入れて乳棒で適宜粉砕することで粉末の非晶質クルクミンを含むクルクミンとヒドロキシプロピルメチルセルロースとの複合体を調製した（実施例７）。
なお、水溶性セルロース誘導体であるヒドロキシプロピルメチルセルロースの代わりにメチルセルロースを用いて複合体を調製した場合を比較例１とした。 (3) Preparation method B (drying by air drying)
After 2.0 g of hydroxypropylmethylcellulose (HPMC: Metrolose SE-06, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in 200 mL of pure water, the pH of the aqueous solution was adjusted to 13 using a 10 mol / L sodium hydroxide aqueous solution. After adding 2.2 g of turmeric extract powder having a curcumin content of 91.2% (w / w) provided by San-Ei Gen FFI Co., Ltd. A complex of curcumin containing amorphous curcumin and hydroxypropylmethylcellulose was prepared by adjusting the pH of the aqueous solution to 6 using a 10 mol / L hydrochloric acid aqueous solution.
Next, the aqueous solution is centrifuged (2,000 × g, 10 min) to recover the solid content in the aqueous solution, which is placed on a tray and kept in a dark room for about 3 days at room temperature for drying. The dried product was recovered. The dried product was put in a mortar and appropriately pulverized with a pestle to prepare a complex of curcumin containing powdered amorphous curcumin and hydroxypropylmethylcellulose (Example 7).
In addition, the case where the composite_body | complex was prepared using methylcellulose instead of the hydroxypropyl methylcellulose which is a water-soluble cellulose derivative was made into the comparative example 1.
試験例１（複合体中のクルクミン結晶の測定）
調製した各種複合体中のクルクミンの結晶性を粉体Ｘ線回折装置（ＲＩＮＴ－ＵｌｔｉｍａＩＩＩ、Ｒｉｇａｋｕ社製）を用いて調べた。なお、対照として、クルクミン原末、クルクミン原末とヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとを重量比で１：１又は１：３となるように混合して調製した物理混合品Ａ（Ｃｕｒｃｕｍｉｎ：ＨＰＭＣ＝１：１）、Ｂ（Ｃｕｒｃｕｍｉｎ：ＨＰＭＣ＝１：３）及びＣ（Ｃｕｒｃｕｍｉｎ：ＨＰＣ＝１：１）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）粉末、ヒドロキシプロピルセルロース（ＨＰＣ）粉末、メチルセルロース（ＭＣ）粉末並び塩化ナトリウム（ＮａＣｌ）を用いた。 Test Example 1 (Measurement of Curcumin Crystal in Complex)
The crystallinity of curcumin in the prepared various composites was examined using a powder X-ray diffractometer (RINT-Ultima III, manufactured by Rigaku). As a control, curcumin bulk powder, physical mixture A prepared by mixing curcumin bulk powder and hydroxypropylmethylcellulose or hydroxypropylcellulose so that the weight ratio is 1: 1 or 1: 3 (curcumin: HPMC = 1: 1), B (Curcumin: HPMC = 1: 3) and C (Curcumin: HPC = 1: 1), hydroxypropylmethylcellulose (HPMC) powder, hydroxypropylcellulose (HPC) powder, methylcellulose (MC) powder and chlorination Sodium (NaCl) was used.
調製した各種複合体中のクルクミンの結晶性を粉体Ｘ線回折装置（ＲＩＮＴ－ＵｌｔｉｍａＩＩＩ、Ｒｉｇａｋｕ社製）を用いて調べた。なお、対照として、クルクミン原末、クルクミン原末とヒドロキシプロピルメチルセルロース又はヒドロキシプロピルセルロースとを重量比で１：１又は１：３となるように混合して調製した物理混合品Ａ（Ｃｕｒｃｕｍｉｎ：ＨＰＭＣ＝１：１）、Ｂ（Ｃｕｒｃｕｍｉｎ：ＨＰＭＣ＝１：３）及びＣ（Ｃｕｒｃｕｍｉｎ：ＨＰＣ＝１：１）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）粉末、ヒドロキシプロピルセルロース（ＨＰＣ）粉末、メチルセルロース（ＭＣ）粉末並び塩化ナトリウム（ＮａＣｌ）を用いた。 Test Example 1 (Measurement of Curcumin Crystal in Complex)
The crystallinity of curcumin in the prepared various composites was examined using a powder X-ray diffractometer (RINT-Ultima III, manufactured by Rigaku). As a control, curcumin bulk powder, physical mixture A prepared by mixing curcumin bulk powder and hydroxypropylmethylcellulose or hydroxypropylcellulose so that the weight ratio is 1: 1 or 1: 3 (curcumin: HPMC = 1: 1), B (Curcumin: HPMC = 1: 3) and C (Curcumin: HPC = 1: 1), hydroxypropylmethylcellulose (HPMC) powder, hydroxypropylcellulose (HPC) powder, methylcellulose (MC) powder and chlorination Sodium (NaCl) was used.
結果を図１～３に示す。図１～２に示したように、本発明方法により得られる複合体中のクルクミンは非晶質になっていることがわかる。また、図３で示したように、水溶性セルロース誘導体としてメチルセルロースを用いた場合（比較例１）では、ヒドロキシプロピルメチルセルロースを用いた場合（実施例７）と比べて、クルクミンの結晶を示す数多くのピークが認められた（比較例１の丸枠内）。この結果から、水溶性セルロース誘導体としてヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロースを用いることがクルクミンの非晶質化に有効であることが分かった。
The results are shown in Figs. As shown in FIGS. 1 and 2, it can be seen that the curcumin in the composite obtained by the method of the present invention is amorphous. In addition, as shown in FIG. 3, in the case of using methylcellulose as the water-soluble cellulose derivative (Comparative Example 1), a number of crystals showing curcumin are larger than in the case of using hydroxypropylmethylcellulose (Example 7). A peak was observed (inside the round frame of Comparative Example 1). From this result, it was found that using hydroxypropylmethylcellulose and / or hydroxypropylcellulose as the water-soluble cellulose derivative is effective for making a curcumin amorphous.
試験例２（各種非晶質クルクミン含有複合体の吸収性）
（１）供試動物
供試動物は、６週齢のＳＤラット（雄性、体重約２００ｇ、日本チャールス・リバー社）を用いた。
（２）投与方法
投与方法は、投与前１２時間以上絶食させた供試動物（ｎ＝３又は５）に、上記２．で調製した非晶質クルクミンを含むクルクミン－ヒドロキシプロピルメチルセルロース複合体又はクルクミン－ヒドロキシプロピルセルロース複合体をそれぞれクルクミン濃度３．３ｍｇ／ｍＬとなるように所定量を注射用水に添加して６ｍＬにメスアップし、超音波発生装置を用いて混合した後、クルクミン投与用量が１０ｍｇ／ｋｇとなるように経口ゾンデを用いて強制的に経口投与した（試験例１～６）。なお、クルクミン原末を投与した場合（比較試験例１）及びクルクミン原末とヒドロキシプロピルメチルセルロース粉末とを単に物理的に混合（クルクミン：ヒドロキシプロピルメチルセルロース＝１：３）した物理混合物（比較試験例２）を対照とした。 Test Example 2 (Absorptivity of various amorphous curcumin-containing composites)
(1) Test animal As test animals, 6-week-old SD rats (male, body weight of about 200 g, Japan Charles River) were used.
(2) Administration method The administration method is as described in 2. above for test animals (n = 3 or 5) fasted for 12 hours or more before administration. Add a predetermined amount of curcumin-hydroxypropylmethylcellulose complex or curcumin-hydroxypropylcellulose complex containing amorphous curcumin prepared in step 1 to water for injection to a concentration of 3.3 mg / mL, and make up to 6 mL. Then, after mixing using an ultrasonic generator, oral administration was forcibly administered using an oral sonde so that the dose of curcumin was 10 mg / kg (Test Examples 1 to 6). When curcumin bulk powder was administered (Comparative Test Example 1) and a physical mixture (curcumin: hydroxypropylmethylcellulose = 1: 3) simply mixed with curcumin bulk powder and hydroxypropyl methylcellulose powder (Comparative Test Example 2) ) As a control.
（１）供試動物
供試動物は、６週齢のＳＤラット（雄性、体重約２００ｇ、日本チャールス・リバー社）を用いた。
（２）投与方法
投与方法は、投与前１２時間以上絶食させた供試動物（ｎ＝３又は５）に、上記２．で調製した非晶質クルクミンを含むクルクミン－ヒドロキシプロピルメチルセルロース複合体又はクルクミン－ヒドロキシプロピルセルロース複合体をそれぞれクルクミン濃度３．３ｍｇ／ｍＬとなるように所定量を注射用水に添加して６ｍＬにメスアップし、超音波発生装置を用いて混合した後、クルクミン投与用量が１０ｍｇ／ｋｇとなるように経口ゾンデを用いて強制的に経口投与した（試験例１～６）。なお、クルクミン原末を投与した場合（比較試験例１）及びクルクミン原末とヒドロキシプロピルメチルセルロース粉末とを単に物理的に混合（クルクミン：ヒドロキシプロピルメチルセルロース＝１：３）した物理混合物（比較試験例２）を対照とした。 Test Example 2 (Absorptivity of various amorphous curcumin-containing composites)
(1) Test animal As test animals, 6-week-old SD rats (male, body weight of about 200 g, Japan Charles River) were used.
(2) Administration method The administration method is as described in 2. above for test animals (n = 3 or 5) fasted for 12 hours or more before administration. Add a predetermined amount of curcumin-hydroxypropylmethylcellulose complex or curcumin-hydroxypropylcellulose complex containing amorphous curcumin prepared in step 1 to water for injection to a concentration of 3.3 mg / mL, and make up to 6 mL. Then, after mixing using an ultrasonic generator, oral administration was forcibly administered using an oral sonde so that the dose of curcumin was 10 mg / kg (Test Examples 1 to 6). When curcumin bulk powder was administered (Comparative Test Example 1) and a physical mixture (curcumin: hydroxypropylmethylcellulose = 1: 3) simply mixed with curcumin bulk powder and hydroxypropyl methylcellulose powder (Comparative Test Example 2) ) As a control.
（３）血漿中クルクミン濃度の測定
血漿中クルクミン及び／又はその類縁体濃度の測定は、投与開始０．５時間、１時間及び／又は２時間後に供試動物の頸静脈から無麻酔下で約０．５ｍＬ採血を行うことで得たヘパリン血漿を用いて、以下の方法によって測定した。
ａ．前処理
採血した血漿２０μＬに０．１Ｍ酢酸緩衝液（ｐＨ５．０）１００μＬとβ－グルクロニダーゼ溶液（約６８，０００ｕｎｉｔｓ／ｍＬ）１０μＬを加え、３７℃で１時間保持した。その後、内部標準液であるメプロニル２０ｎｇ／ｍＬが含まれる５０％（v/v）メタノール１０μＬとクロロホルム０．５ｍＬとを添加し、ボルテックスミキサーを用いて１分間撹拌後、超音波発生装置を用いて１５分間混合することで抽出処理した抽出処理液を遠心分離（１３，０００×ｇ、５分間、室温）によってクロロホルム層と水層とに分離した。さらに、この分離した水層について、上記同様にクロロホルムを添加することによって抽出する抽出処理を行った。次いで、該クロロホルム層を採取し、これを減圧遠心濃縮機を用いて溶媒を留去することで乾固させ、ここに５０％（v/v）メタノール１００μＬを添加した後、遠心分離（１３，０００×ｇ、５分間、室温）して上清液を回収した。
ｂ．測定方法
上記４．（３）ａ．で調製した上清液２μＬをＬＣ－ＭＳ／ＭＳ（島津社製）を用いて分析を行うことで血漿中クルクミン濃度を測定した。なお、ＬＣ－ＭＳ／ＭＳ分析条件は、ＬＣカラムがＡｔｌａｎｔｉｓ Ｔ３（２．１×１５０ｍｍ，３μｍ，Ｗａｔｅｒｓ社製）、カラム温度が４０℃、流速が０．２ｍＬ／ｍｉｎ、移動相がＡ：０．１％ギ酸水溶液、Ｂ：０．１％ギ酸／アセトニトリルとし、表３の条件でグラジェント溶出を行った。また、ＭＳ分析条件は、イオン化モードがElectron Spray thermo ionization（ＥＳＩ）、Positive、測定モードがMultiple Reaction Monitoring（ＭＲＭ）とし、クルクミン３６９．１→１７７．２（ｍ／ｚ）、メプロニル２７０→１１９（ｍ／ｚ）で評価した。
一方、試料中に含まれるクルクミン量を定量するために使用する検量線の作成は、クルクミンが１．０、２．０、３．９、７．８、１５．６、３１．３、６２．５、１２５又は２５０ｎｇ／ｍＬを含む５０％（ｖ／ｖ）メタノール溶液（クルクミン標準液）９０μＬにメプロニル２０ｎｇ／ｍＬを含む５０％エタノール溶液１０μＬを添加することで調製した各種標準溶液（クルクミン濃度０．９～２２５ｎｇ／ｍＬ）を用いて上記同様の条件で測定することで行った。 (3) Measurement of plasma curcumin concentration The measurement of plasma curcumin and / or its analog concentration is about 0.5 hour, 1 hour and / or 2 hours after the start of administration, from the jugular vein of the test animal under anesthesia. Using heparin plasma obtained by taking 0.5 mL of blood, measurement was performed by the following method.
a. Pretreatment 100 μL of 0.1 M acetate buffer (pH 5.0) and 10 μL of β-glucuronidase solution (about 68,000 units / mL) were added to 20 μL of the collected plasma and held at 37 ° C. for 1 hour. Thereafter, 10 μL of 50% (v / v) methanol containing 0.5 ng / mL of mepronil as an internal standard solution and 0.5 mL of chloroform were added, stirred for 1 minute using a vortex mixer, and then using an ultrasonic generator. The extraction processing liquid extracted by mixing for 15 minutes was separated into a chloroform layer and an aqueous layer by centrifugation (13,000 × g, 5 minutes, room temperature). Further, the separated aqueous layer was extracted by adding chloroform in the same manner as described above. Next, the chloroform layer was collected, and this was dried by evaporating the solvent using a vacuum centrifugal concentrator. After adding 100 μL of 50% (v / v) methanol, centrifugation (13, 000 × g, 5 minutes, room temperature) to recover the supernatant.
b. Measurement method 4. (3) a. The plasma curcumin concentration was measured by analyzing 2 μL of the supernatant prepared in step 1 using LC-MS / MS (manufactured by Shimadzu Corporation). The LC-MS / MS analysis conditions were as follows: the LC column was Atlantis T3 (2.1 × 150 mm, 3 μm, manufactured by Waters), the column temperature was 40 ° C., the flow rate was 0.2 mL / min, and the mobile phase was A: 0. .1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile, and gradient elution was performed under the conditions shown in Table 3. The MS analysis conditions were as follows: ionization mode was Electron Spray thermoionization (ESI), Positive, measurement mode was Multiple Reaction Monitoring (MRM), curcumin 369.1 → 177.2 (m / z), mepronil 270 → 119 ( m / z).
On the other hand, the calibration curve used for quantifying the amount of curcumin contained in the sample is 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62. Various standard solutions (curcumin concentration 0) prepared by adding 10 μL of 50% ethanol solution containing 20 ng / mL mepronil to 90 μL of 50% (v / v) methanol solution (curcumin standard solution) containing 5, 125 or 250 ng / mL 9 to 225 ng / mL) under the same conditions as described above.
血漿中クルクミン及び／又はその類縁体濃度の測定は、投与開始０．５時間、１時間及び／又は２時間後に供試動物の頸静脈から無麻酔下で約０．５ｍＬ採血を行うことで得たヘパリン血漿を用いて、以下の方法によって測定した。
ａ．前処理
採血した血漿２０μＬに０．１Ｍ酢酸緩衝液（ｐＨ５．０）１００μＬとβ－グルクロニダーゼ溶液（約６８，０００ｕｎｉｔｓ／ｍＬ）１０μＬを加え、３７℃で１時間保持した。その後、内部標準液であるメプロニル２０ｎｇ／ｍＬが含まれる５０％（v/v）メタノール１０μＬとクロロホルム０．５ｍＬとを添加し、ボルテックスミキサーを用いて１分間撹拌後、超音波発生装置を用いて１５分間混合することで抽出処理した抽出処理液を遠心分離（１３，０００×ｇ、５分間、室温）によってクロロホルム層と水層とに分離した。さらに、この分離した水層について、上記同様にクロロホルムを添加することによって抽出する抽出処理を行った。次いで、該クロロホルム層を採取し、これを減圧遠心濃縮機を用いて溶媒を留去することで乾固させ、ここに５０％（v/v）メタノール１００μＬを添加した後、遠心分離（１３，０００×ｇ、５分間、室温）して上清液を回収した。
ｂ．測定方法
上記４．（３）ａ．で調製した上清液２μＬをＬＣ－ＭＳ／ＭＳ（島津社製）を用いて分析を行うことで血漿中クルクミン濃度を測定した。なお、ＬＣ－ＭＳ／ＭＳ分析条件は、ＬＣカラムがＡｔｌａｎｔｉｓ Ｔ３（２．１×１５０ｍｍ，３μｍ，Ｗａｔｅｒｓ社製）、カラム温度が４０℃、流速が０．２ｍＬ／ｍｉｎ、移動相がＡ：０．１％ギ酸水溶液、Ｂ：０．１％ギ酸／アセトニトリルとし、表３の条件でグラジェント溶出を行った。また、ＭＳ分析条件は、イオン化モードがElectron Spray thermo ionization（ＥＳＩ）、Positive、測定モードがMultiple Reaction Monitoring（ＭＲＭ）とし、クルクミン３６９．１→１７７．２（ｍ／ｚ）、メプロニル２７０→１１９（ｍ／ｚ）で評価した。
一方、試料中に含まれるクルクミン量を定量するために使用する検量線の作成は、クルクミンが１．０、２．０、３．９、７．８、１５．６、３１．３、６２．５、１２５又は２５０ｎｇ／ｍＬを含む５０％（ｖ／ｖ）メタノール溶液（クルクミン標準液）９０μＬにメプロニル２０ｎｇ／ｍＬを含む５０％エタノール溶液１０μＬを添加することで調製した各種標準溶液（クルクミン濃度０．９～２２５ｎｇ／ｍＬ）を用いて上記同様の条件で測定することで行った。 (3) Measurement of plasma curcumin concentration The measurement of plasma curcumin and / or its analog concentration is about 0.5 hour, 1 hour and / or 2 hours after the start of administration, from the jugular vein of the test animal under anesthesia. Using heparin plasma obtained by taking 0.5 mL of blood, measurement was performed by the following method.
a. Pretreatment 100 μL of 0.1 M acetate buffer (pH 5.0) and 10 μL of β-glucuronidase solution (about 68,000 units / mL) were added to 20 μL of the collected plasma and held at 37 ° C. for 1 hour. Thereafter, 10 μL of 50% (v / v) methanol containing 0.5 ng / mL of mepronil as an internal standard solution and 0.5 mL of chloroform were added, stirred for 1 minute using a vortex mixer, and then using an ultrasonic generator. The extraction processing liquid extracted by mixing for 15 minutes was separated into a chloroform layer and an aqueous layer by centrifugation (13,000 × g, 5 minutes, room temperature). Further, the separated aqueous layer was extracted by adding chloroform in the same manner as described above. Next, the chloroform layer was collected, and this was dried by evaporating the solvent using a vacuum centrifugal concentrator. After adding 100 μL of 50% (v / v) methanol, centrifugation (13, 000 × g, 5 minutes, room temperature) to recover the supernatant.
b. Measurement method 4. (3) a. The plasma curcumin concentration was measured by analyzing 2 μL of the supernatant prepared in step 1 using LC-MS / MS (manufactured by Shimadzu Corporation). The LC-MS / MS analysis conditions were as follows: the LC column was Atlantis T3 (2.1 × 150 mm, 3 μm, manufactured by Waters), the column temperature was 40 ° C., the flow rate was 0.2 mL / min, and the mobile phase was A: 0. .1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile, and gradient elution was performed under the conditions shown in Table 3. The MS analysis conditions were as follows: ionization mode was Electron Spray thermoionization (ESI), Positive, measurement mode was Multiple Reaction Monitoring (MRM), curcumin 369.1 → 177.2 (m / z), mepronil 270 → 119 ( m / z).
On the other hand, the calibration curve used for quantifying the amount of curcumin contained in the sample is 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62. Various standard solutions (curcumin concentration 0) prepared by adding 10 μL of 50% ethanol solution containing 20 ng / mL mepronil to 90 μL of 50% (v / v) methanol solution (curcumin standard solution) containing 5, 125 or 250 ng / mL 9 to 225 ng / mL) under the same conditions as described above.
表４に、血漿中のクルクミン濃度（ｎｇ／ｍＬ）、最高血中濃度（Ｃｍａｘ（ｎｇ／ｍＬ））及び血中濃度－時間曲線下面積（ＡＵＣ（ｎｇ／ｍＬ・０－２ｈｒ））を示す。本発明により得られる複合体の経口吸収性は、クルクミン原末及び物理混合物に比べて顕著に向上していることがわかる。
Table 4 shows the curcumin concentration in plasma (ng / mL), the maximum blood concentration (Cmax (ng / mL)), and the area under the blood concentration-time curve (AUC (ng / mL · 0-2hr)). . It can be seen that the oral absorbability of the complex obtained by the present invention is remarkably improved as compared with the curcumin bulk powder and the physical mixture.
Claims (5)
- クルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとをｐＨ１２以上の水溶液に溶解させる工程と、該溶液のｐＨを７以下にする工程と、を有することを特徴とする、非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 A step of dissolving curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an aqueous solution having a pH of 12 or more, and a step of bringing the pH of the solution to 7 or less. A method for producing a complex of curcumin and / or its analog containing crystalline curcumin and / or its analog and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
- さらに、前記ｐＨ７以下とした溶液から水分を取り除く乾燥工程を有する、請求項１に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 The curcumin containing the amorphous curcumin and / or analog thereof according to claim 1 and / or the analog thereof and hydroxypropyl methylcellulose and / or the drying step of removing water from the solution having a pH of 7 or less. A method for producing a composite with hydroxypropylcellulose.
- 前記類縁体が、ビスデメトキシクルクミン、デメトキシクルクミン及びテトラヒドロクルクミンからなる群から選択された少なくとも１種である、請求項１又は２に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 The amorphous curcumin and / or its analog according to claim 1 or 2, wherein the analog is at least one selected from the group consisting of bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin. A method for producing a complex of curcumin and / or an analog thereof and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
- 前記クルクミン及び／又はその類縁体（Ａ）と前記ヒドロキシプロピルメチルセルロース及び／又はヒドロキシプロピルセルロース（Ｂ）との含有比率（Ａ／Ｂ）が、０．１～１０である、請求項１～３のいずれか１項に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 The content ratio (A / B) of the curcumin and / or its analog (A) to the hydroxypropylmethylcellulose and / or hydroxypropylcellulose (B) is 0.1 to 10. A method for producing a composite of curcumin and / or an analog thereof containing the amorphous curcumin and / or an analog thereof according to any one of the above, and hydroxypropylmethylcellulose and / or hydroxypropylcellulose.
- 前記乾燥工程が、噴霧乾燥、減圧乾燥又は風乾である請求項１～４のいずれか１項に記載の非晶質クルクミン及び／又はその類縁体を含有するクルクミン及び／又はその類縁体とヒドロキシプロピルメチルセルロース及び/又はヒドロキシプロピルセルロースとの複合体の製造方法。 The curcumin and / or its analog and hydroxypropyl containing the amorphous curcumin and / or its analog according to any one of claims 1 to 4, wherein the drying step is spray drying, vacuum drying or air drying. A method for producing a complex with methylcellulose and / or hydroxypropylcellulose.
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| WO2019160146A1 (en) | 2018-02-19 | 2019-08-22 | 株式会社セラバリューズ | Oral ingestion composition |
| CN110381932A (en) * | 2017-03-03 | 2019-10-25 | 三荣源有限公司 | Evaluation method containing curcumin preparation and its absorbability or stripping property |
| EP4023246A4 (en) * | 2019-08-30 | 2023-10-04 | San-Ei Gen F.F.I., INC. | Solid composition containing amorphous, poorly water-soluble material, and method for producing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110381932A (en) * | 2017-03-03 | 2019-10-25 | 三荣源有限公司 | Evaluation method containing curcumin preparation and its absorbability or stripping property |
| WO2019160146A1 (en) | 2018-02-19 | 2019-08-22 | 株式会社セラバリューズ | Oral ingestion composition |
| CN111726992A (en) * | 2018-02-19 | 2020-09-29 | 热值株式会社 | Composition for oral intake |
| KR20200122297A (en) | 2018-02-19 | 2020-10-27 | 테라벨류스 코포레이션 | Composition for oral ingestion |
| JPWO2019160146A1 (en) * | 2018-02-19 | 2021-02-25 | 株式会社セラバリューズ | Composition for ingestion |
| EP3756471A4 (en) * | 2018-02-19 | 2021-11-10 | Theravalues Corporation | Oral ingestion composition |
| JP7072905B2 (en) | 2018-02-19 | 2022-05-23 | 株式会社セラバリューズ | Composition for ingestion |
| US11672770B2 (en) | 2018-02-19 | 2023-06-13 | Theravalues Corporation | Oral ingestion composition |
| AU2019222350B2 (en) * | 2018-02-19 | 2023-11-16 | Theravalues Corporation | Oral ingestion composition |
| CN111726992B (en) * | 2018-02-19 | 2024-02-23 | 热值株式会社 | Oral composition |
| EP4023246A4 (en) * | 2019-08-30 | 2023-10-04 | San-Ei Gen F.F.I., INC. | Solid composition containing amorphous, poorly water-soluble material, and method for producing same |
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